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dc.contributor.authorBanerjee, Anirban
dc.contributor.authorLi, Dongge
dc.contributor.authorGuo, Yizhan
dc.contributor.authorMei, Zhongcheng
dc.contributor.authorLau, Christine
dc.contributor.authorChen, Kelly
dc.contributor.authorWestwick, John
dc.contributor.authorKlauda, Jeffery B
dc.contributor.authorSchrum, Adam
dc.contributor.authorLazear, Eric R
dc.contributor.authorKrupnick, Alexander S
dc.date.accessioned2022-05-25T12:29:52Z
dc.date.available2022-05-25T12:29:52Z
dc.date.issued2022-05-23
dc.identifier.urihttp://hdl.handle.net/10713/18994
dc.description.abstractCytokine therapy is limited by undesirable off-target side effects as well as terminal differentiation and exhaustion of chronically stimulated T cells. Here, we describe the signaling properties of a potentially unique cytokine by design, where T cell surface binding and signaling are separated between 2 different families of receptors. This fusion protein cytokine, called OMCPmutIL-2, bound with high affinity to the cytotoxic lymphocyte-defining immunoreceptor NKG2D but signaled through the common γ chain cytokine receptor. In addition to precise activation of cytotoxic T cells due to redirected binding, OMCPmutIL-2 resulted in superior activation of both human and murine CD8+ T cells by improving their survival and memory cell generation and decreasing exhaustion. This functional improvement was the direct result of altered signal transduction based on the reorganization of surface membrane lipid rafts that led to Janus kinase-3-mediated phosphorylation of the T cell receptor rather than STAT/AKT signaling intermediates. This potentially novel signaling pathway increased CD8+ T cell response to low-affinity antigens, activated nuclear factor of activated T cells transcription factors, and promoted mitochondrial biogenesis. OMCPmutIL-2 thus outperformed other common γ chain cytokines as a catalyst for in vitro CD8+ T cell expansion and in vivo CD8+ T cell-based immunotherapy.en_US
dc.description.urihttps://doi.org/10.1172/jci.insight.158889en_US
dc.language.isoenen_US
dc.publisherAmerican Society for Clinical Investigationen_US
dc.relation.ispartofJCI Insighten_US
dc.subjectCytokinesen_US
dc.subjectImmunologyen_US
dc.subjectImmunotherapyen_US
dc.subjectTherapeuticsen_US
dc.titleA reengineered common chain cytokine augments CD8+ T cell-dependent immunotherapy.en_US
dc.typeArticleen_US
dc.identifier.doi10.1172/jci.insight.158889
dc.identifier.pmid35603788
dc.source.journaltitleJCI insight
dc.source.volume7
dc.source.issue10
dc.source.countryUnited States


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